Method for preparing methyl 2-diphenylmethylsulfinylacetate

ABSTRACT

The invention relates to a method for preparing methyl 2-diphenylmethylsulfinylacetate (MDMSA) comprising the steps of: (i) conversion of benzhydrol into methyldiphenylmethylthioacetate (MDMTA); and (ii) conversion of methyldiphenylmethylthioacetate (MDMTA) into methyl-2-diphenylmethylsulfinylacetate by oxidation, according to the following sequence: benzhydrol→MDMTA→MDMSA.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application represents entry into the U.S. national chase ofInternational Application No. PCT/IB2004/000002, filed Jan. 8, 2004,which in turn claimed priority of European Application No. EP03290082.1, filed Jan. 13, 2003.

FIELD OF THE INVENTION

The present invention relates to a novel method for preparing methyl2-diphenylmethylsulfinylacetate (MDMSA).

BACKGROUND OF THE INVENTION

MDMSA is disclosed as an intermediate compound in the synthesis ofmodafinil also known as 2-[(diphenylmethyl)sulfinyl]acetamide. Modafinilwhich is a synthetic acetamide with wake-promoting activity, is usefulin the treatment of narcolepsy, among other disorders.

The inventors have now discovered a novel route for synthesizing MDMSAwhich is applicable at the industrial scale.

Advantageously, the MDMSA can be obtained in two or three steps, eachbeing characterized by high yields.

In an advantageous embodiment, these steps may be carried out in thesame reactor and the same solvent, without isolating the intermediatecompounds.

The aim of the present invention is to provide an economical andefficient method for preparing MDMSA.

SUMMARY OF THE INVENTION

These aims and others are achieved by the present invention whichrelates to a method for preparing methyl 2-diphenylmethylsufinylacetatecomprising the steps of:

-   -   (i) conversion of benzhydrol into        methyldiphenylmethylthioacetate; and    -   (ii) conversion of methyldiphenylmethylthioacetate into        methyl-2-diphenylmethylsulfinylacetate by oxidation.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Scheme 1 illustrates in general the steps used in this method:

The reactions of steps (i) and (ii) used in this method are carried outin an appropriate solvent which may be easily chosen by persons skilledin the art, it being understood that an appropriate solvent denotes asolvent which is nonreactive towards the starting reagents, theintermediates or the products, at the reaction temperature considered,it being possible for the latter to vary from the solidification pointof the solvent to the boiling point of the solvent.

A given reaction may be carried out in a solvent or in a mixture ofseveral solvents, the solvent(s) being generally chosen according to thetype of reaction considered and the subsequent treatment of the reactionmedium.

In a preferred embodiment, the solvent is an aprotic solvent.

By way of illustration and without limitation of aprotic solvents whichmay be suitable for the method according to the invention, there may bementioned in particular chlorinated solvents, aromatic solvents,hydrocarbon solvents and ethereal solvents.

Among the chlorinated solvents, chloroform, dichloromethane orchlorobenzene may be mentioned in particular.

Among the appropriate aromatic solvents, there may be mentioned, forexample, benzene, toluene and chlorobenzene.

As examples of appropriate hydrocarbon solvents, cyclohexane, pentaneand hexane may be mentioned.

Solvents such as diethyl ether, tetrahydrofuran and dioxane are usefulas ethereal solvents.

Step (i) and (ii) may be conducted separately, notably in differentsolvents, where each intermediate is independently isolated.

In an advantageous embodiment, the reaction steps are conducted in thesame reactor and without isolation of any intermediates.

Step i)

In a preferred embodiment, the conversion of benzhydrol into methyldiphenylmethylthioacetate comprises two steps of:

-   -   a1) conversion of benzhydrol into a benzhydryl carboxylate; and    -   b1) conversion of benzhydryl carboxylate into methyl        diphenylmethyl thioacetate.

Scheme 2 illustrates in general steps a1) and b1) used in this method:

Step a1)

In one preferred embodiment, step a1) comprises reacting benzhydrol andan acid anhydride in the presence of an inorganic acid and in anappropriate solvent, preferably aprotic.

In the context of the present invention, dichloromethane is particularlypreferred for its advantageous properties of extraction, distillation atlow temperature, its nonflammability, its chemical neutrality and itscapacity to be easily recycled in the context of this method.

Generally, the acid anhydride and the aprotic solvent are loadedsimultaneously into the reactor, at a temperature of about 20° C.

The acid anhydrides for the purposes of the present description denoteeither symmetric anhydrides of monocarboxylic acids, mixed anhydrides,or cyclic anhydrides of polycarboxylic acids.

By way of examples of acid anhydrides which may be suitable in step a1)according to the invention, there may be mentioned in particular aceticanhydride, butyric anhydride and propanoic anhydride, acetic anhydridebeing particularly preferred.

The preferred reaction conditions are those which provide for the use ofan equimolar quantity of acid anhydride relative to the benzhydrol inthe aprotic solvent.

However, it is preferable to carry out the procedure in the presence ofa slight excess of acid anhydride. An excessively high excess may indeedinduce the formation of by-products in the subsequent steps of themethod while an excessively small quantity is capable of slowing thekinetics of the oxidation reaction carried out in step (ii). Thus, themolar ratio of acid anhydride preferably varies between 1 and 1.2, evenbetter between 1 and 1.1, and is advantageously 1.05, which correspondsto the optimum molar ratio of acid anhydride which makes it possible toobtain a clean synthesis.

Preferably, the procedure is carried out in the presence of a volume ofsolvent varying from 1.5 to 5 volumes, optimally in the presence ofabout 2 volumes. Under these conditions, the dilution brought aboutpromotes the formation of the carboxylate.

According to an equally preferred variant of step a), the inorganic acidused is chosen from hydrochloric acid, hydrobromic acid, o-phosphoricacid and sulphuric acid, sulphuric acid being particularly preferred, inparticular in the form of a 96% aqueous solution.

Preferably, the procedure is carried out in the presence of a quantityof inorganic acid ranging from 0.02 to 0.3 molar equivalents relative tothe benzhydrol, even better from 0.05 to 0.15 equivalents.

As a safety precaution, the inorganic acid is generally introduced at atemperature of about 0° C. so as to control the exothermicity of thereaction.

The benzhydrol is then loaded at a sufficient temperature to allow asufficiently rapid reaction kinetics, but not too high so as to avoidthe formation of by-products such as benzhydryl ether. It isparticularly preferable to carry out the procedure at a temperature ofbetween −5° C. and +5° C., even better between −2° C. and +2° C. for anintroduction time ranging from 45 minutes to 2 hours, preferably inabout 1 hour. This introduction time indeed makes it possible to controlthe exothermicity of the reaction and to limit the formation ofby-products.

The benzhydrol is generally maintained at this temperature for asufficient contact time to obtain a complete reaction, but not too highin order to avoid the degradation of the benzhydryl carboxylate. Theexpression “complete reaction”, for the purposes of the presentinvention, is understood to mean a reaction leading to the production ofthe derived product with a conversion rate greater than 99.2%, andpreferably greater than 99.5%. In general, a complete reaction isobtained after a contact time of 2 hours.

The benzhydryl carboxylate obtained can be immediately used in the nextstep, without intermediate isolation.

Step a1) can also be realized by any other appropriate method.

As an example, step a1) can be realized by reacting benzhydrol with acarboxylic acid, for instance:

-   -   2-methyl-butyric acid in combination with:        -   SOCl₂, pyridine, in benzene; or        -   H₂SO₄ in dichloromethane; or        -   TsOH in benzene            as disclosed in the reference: Fujita S. and al., Bull.            Chem. Soc. Jpn 1972, 45: 2571–2574;    -   or acetic acid in combination with potassium iodide as described        in Strazzoli P. et al., Recl. Trav. Chim., The Netherlands,        1991; 1:5–12.

By way of example, step a1) can also be realized by reacting acarboxylic acid salt, for instance acetic acid sodium salt as disclosedin Herzig S., Justus Liebigs, Ann. Chem.; 1921; 422:330.

By way of example, step a1) can also be realized by reacting benzhydrolwith a carboxylic acid chloride, as for example acetyl chloride in thepresence of triethylamine as disclosed in Roizel B. and al., Chem.Commun., 2000, 16:1507–1508.

As an example, step a1) can also be realized by reacting benzhydrol withacetic acid ethyl ester in the presence of Ti(OC₂H₅) (Schnurrenberger P.and al., Helv. Chim. Acta, 1982, 65(4): 1197–1201); or of iron (III)perchlorate (ITP) (Kumar B. and al., Indian J. Chem. Sect. B, 1993,32(2): 292–293); or of Fe(ClO₄)₃, SiO₂ (Parmar and al., Synth. Commun.,1999, 29(1): 139–144).

Step b1)

Step b1) can be performed by any appropriate method.

In a preferred embodiment, step b1) comprises bringing the solutionobtained in step a1) into contact with methyl thioglycolate.

The methyl thioglycolate is generally introduced in about 10 minutes at0° C. but with no temperature restriction (it can then increase to about9° C.). The reaction medium is then heated to a sufficiently hightemperature to drive the reaction kinetics, but not too high so as toavoid the formation of by-products. Generally, the procedure is carriedout at a temperature of between 15° C. and 25° C., preferably between18° C. and 22° C., and contact is maintained at this temperature for asufficient time to obtain complete reaction, with few by-products,generally for 2 to 3 hours, preferably for a period of 2 hours.

The methyl diphenylthioacetate can be used in step (ii) withoutintermediate isolation.

In another preferred embodiment, step i) comprises two steps of:

-   -   a2) conversion of benzhydrol into benzhydryl carboxylic acid;    -   b2) conversion of benzhydryl carboxylic acid into methyl        diphenylmethylthioacetate.

This method is illustrated by scheme 3:

Step a2)

Step a2) may be realized according to any appropriate method and notablyaccording to conditions disclosed in: Dahlbom O., Acta Chem. Scand.,1948, 2: 856–858; Carceller E. et al., J. Med. Chem., 1993; 36:2984–2997; Lisac S. et al., J. Organomet. Chem. 1996, 507: 215–220;Okarvi S. et al., J. Labelled Compd. Radiopharm, 1997, 39: 853–874;Patent Thomae GmbH DE 2812542, 1979, Chem. Abstract 1980; 92; 198165;Iskander, Y. et al., J. Chem. Soc., 1961, 2397–2402.

In a particular embodiment, step a2) is realized by reacting benzhydrolwith thioacetic acid, in the presence of an organic or inorganic acid.

Preferably, the solvent is a protic solvent, more preferably acarboxylic acid and notably acetic acid.

Inorganic or organic acid is preferably chosen among hydrochloric acid,POCl₃, trifluoroacetic acid, hydrobromic acid, o-phosphoric acid,sulphuric acid, POCl₃ and trifluoroacetic acid being particularlypreferred.

Preferably, the reaction is realized at room temperature.

Step b2)

Esterification reaction of step b2) may be realized by any methods knownfrom the person skilled in the art.

In another particular embodiment, step (i) comprises two steps of:

-   -   a3) conversion of the hydroxyl group of benzhydrol into a        leaving group;    -   b3) conversion of the obtained product into        methyldiphenylmethylthioacetate.

This method is illustrated by scheme 4:

Step a3)

The leaving group in step a3) means any group that can be removed easilyby a nucleophilic reactant. Leaving groups may be selected from thegroup consisting of halogenes, such as chloro- and bromo-radicals, orsulfonyl groups such as methanesulfonyl- or p-toluenesulfonyl-radicals.

Step a3) may be realized by any methods known from the person skilled inthe art.

As an example, hydroxyl group of benzhydrol may be converted intochloro- or bromo-radical by reacting benzhydrol with thionyl choride orthionyl bromide.

As an example, hydroxyl group of benzhydrol may be converted intomethanesulfonate group or into p-toluenesulfonate group by reactingbenzhydrol respectively with methanesulfonyl chloride orp-toluenesulfonyl chloride.

Step b3)

In a preferred embodiment, step b3) is realized according to conditionsof step b1).

Step b3) may also be realized by any other appropriate method.

In another preferred embodiment, step i) comprises reacting benzhydrolwith methylthioglycolate in the presence of a metallic catalyst in asolvent, as illustrated by scheme 5:

Preferably, the metallic catalyst is chosen from ZnCl₂, ZnBr₂, ZnI₂,ZnI₂ being particularly preferred.

Preferably, the solvent is chosen from aprotic solvents, more preferablyfrom halogenated solvent and particularly chlorinated solvents such asdichloromethane, dichloroethane.

Step ii)

Inventors have now settled oxidation conditions that allow interestinglyto control the conversion of methyldiphenylmethylthioacetate intomethyl-2-diphenylmethylsulfinylacetate, notably formation ofby-products, yields and kinetics of the reaction.

Various parameters used in step (ii) capable of influencing theefficiency of the reaction may be optimized, such as the quantity ofoxidizing agent introduced, the dilution of the reaction medium, thereaction temperature, the contact time and the acidity of the reactionmedium.

Thus, in general, an excessively small quantity of oxidizing agent meansan incomplete reaction. Conversely, an excessively large excess promotesthe formation of the dioxidized by-product, sulfone.

By way of illustration of oxidizing agents which may be suitable for theinvention, there may be mentioned in particular oxone, potassiumpermanganate, sodium percarbonate, peroxides such as hydrogen peroxide,tert-butyl hydroperoxide and m-chloroperoxybenzoic acid, hydrogenperoxide being particularly preferred.

In a preferred embodiment, step ii) is performed in dichloromethane.

According to a preferred embodiment, the oxidizing agent used in step(ii) is hydrogen peroxide, preferably in the form of a 35% aqueoussolution. Indeed, a lower titre causes a higher dilution, which candecrease the kinetics of the reaction.

Although a stoichiometric quantity of oxidizing agent is sufficient, itis preferably to carry out the procedure in the presence of a slightexcess, preferably in the presence of a molar ratio of between 1 and1.1.

The acidity of the medium results from the operating conditions of step(i).

The reaction temperature can influence the kinetics of the oxidationreaction. Thus, it is preferable that the temperature is between 28° C.and 37° C., the temperature range for which the reaction kinetics isparticularly increased taking into account the acidity of the medium.

Preferably, a reaction temperature of between 28° C. and 32° C. ispreferred. This temperature indeed makes it possible to have optimumcontrol of the method, in particular the stopping point beyond whichsuperoxidation becomes non-negligible.

The contact time in order to obtain a clean and complete reaction mayvary according to the scale of operation and also according to thequantity of inorganic acid, in particular of sulfuric acid, present inthe reaction medium at step b).

Preferably, the reaction is considered as being “complete” in step (ii)when the ratio R₁=nonoxidizedderivative/(monooxidized+dioxidized+nonoxidized derivative)<0.5%.

The expression “clean” reaction is understood to mean, for the purposesof the present description, a reaction in which the ratio R₂=dioxidizedderivative/(monooxidized+dioxidized+nonoxidized derivative)<0.5%.

The contact time necessary in order to obtain a clean and completereaction may be determined using conventional analytical techniqueswhich make it possible to monitor the progress of the reaction, such asHPLC (High-Performance Liquid Chromatography), IR (Infrared) or NMR(Nuclear Magnetic Resonance).

In general, the contact time necessary and sufficient to obtain a cleanand complete reaction is less than 35 hours, preferably less than orequal to 33 hours, so as to avoid the formation of by-products such asin particular diphenylmethylthioacetic acid, and greater than 20 hours,preferably greater than or equal to 25 hours.

Of course, it is within the capability of persons skilled in the art toadjust the contact time necessary for obtaining a complete reaction atthe scale of operation considered.

An increase in the quantity of inorganic acid in the reaction medium cannevertheless make it possible to significantly reduce the oxidationreaction time.

Without wishing to be limited to any theory, a hypothesis which makes itpossible to explain this unexpected effect is that the inorganic acidplays a catalyst role in the mechanism of oxidation by the oxidizingagent. By way of example, in the case of sulphuric acid, it is assumedthat a reaction intermediate of the H₂SO₅ type is formed in the medium,transferring oxygen either directly to the oxidizable species, orindirectly by an accelerated formation of peracetic acid.

Thus, according to a preferred variant of step (ii) of the methodaccording to the invention, an additional quantity of inorganic acid,preferably of 0.02 to 0.3 molar equivalents, and more preferably of 0.05to 0.15 molar equivalents is added to the reaction medium in step b1),generally prior to the introduction of the oxidizing agent. Anacceleration of the reaction kinetics is then observed.

Advantageously, the contact time required which is sufficient to obtaina complete and clean reaction in step (ii) is considerably reduced andis generally between 10 and 13 hours.

Advantageously, the introduction of the inorganic acid in two portionsmakes it possible to reduce the acidity of the reaction medium in stepsa1) and b1) and therefore to limit the formation of by-products.

Step (iii)

In a further embodiment, the method according to the invention comprisesan additional step of iii) recovering the methyl2-diphenyl-methylsulfinylacetate obtained.

The isolation of the MDMSA formed in step (iii) can be carried outaccording to any conventional method known to persons skilled in theart.

Preferably, the MDMSA is isolated by extraction.

The organic phases are then combined and concentrated under reducedpressure, preferably at a temperature of 70° C.

According to a particular variant, the solvent is distilled to dryness.

The product may be purified according to any method known to personsskilled in the art such as recrystallization or chromatography.

According to a particular embodiment, step (iii) may comprise a step ofdirect crystallization of the MDMSA.

The expression “direct crystallization”, for the purposes of the presentdescription, is understood to mean a crystallization of thenoncrystallized product caused by the addition of appropriate solvents,preferably chosen in particular from methanol, ethanol, ethyl acetate,isopropyl acetate and toluene, isopropyl acetate being particularlypreferred.

In this context, the crystallization solvent is introduced aftersubstantial removal of the aprotic solvent.

Advantageously, this direct crystallization makes it possible to purifythe crude product immediately in the remainder of the method and thus todispense with an isolation step and a more costly subsequent retreatmentstep.

In a particularly preferred embodiment, the method comprises the stepsof:

-   -   i) a1) converting benzhydrol into a benzhydryl carboxylate by        reacting benzhydrol and an acid anhydride in the presence of an        inorganic acid and in an appropriate aprotic solvent;        -   b1) converting the benzhydryl carboxylate into methyl            diphenylmethylthioacetate by bringing the above solution            into contact with methyl thioglycolate;    -   ii) converting the diphenylmethylthioacetate into methyl        2-diphenylmethylsulfinylacetate by bringing the above solution        into contact with an oxidizing agent;        -   and optionally;    -   iii) recovering the methyl 2-diphenylmethylsulfinylacetate        obtained.

This embodiment is illustrated by scheme 6:

Advantageously, the MDMSA is obtained in three successive steps, eachbeing characterized by high yields.

Furthermore, these three steps may be carried out in the same reactorand the same solvent, without isolating the intermediate compounds.

Advantageously, the formation of undesirable by-products is limited andcontrolled according to this method, which makes it possible to dispensewith subsequent reprocessing steps.

Finally, according to another advantageous aspect, this method makes itpossible to reduce the costs of manufacturing MDMSA, in particularbecause of its ease of use, and its high productivity andreproducibility.

The present invention also aims at the MDMSA obtained by the method ofthe invention and particularly by the method implementing:

-   -   i) a1) converting benzhydrol into a benzhydryl carboxylate by        reacting benzhydrol and an acid anhydride in the presence of an        inorganic acid and in an appropriate aprotic solvent;        -   b1) converting the benzhydryl carboxylate into methyl            diphenylmethylthioacetate by bringing the above solution            into contact with methyl thioglycolate;    -   ii) converting the diphenylmethylthioacetate into methyl        2-diphenylmethylsulfinylacetate by bringing the above solution        into contact with an oxidizing agent;        -   and optionally;    -   iii) recovering the methyl 2-diphenylmethylsulfinylacetate        obtained.

The present invention is also directed to a method for preparingmodafinil comprising the steps of:

-   -   (i) conversion of benzhydrol into        methyldiphenylmethylthioacetate; and    -   (ii) conversion of methyldiphenylmethylthioacetate into        methyl-2-diphenylmethylsulfinylacetate by oxidation.

EXAMPLES Example 1 Synthesis of MDMSA on the Laboratory Scale (0.5 l)

a) Benzhydryl Acetate

108.3 g (1.05 mol; 1.05 eq) of acetic anhydride are diluted in 370 ml ofdichloromethane at 20° C. The solution obtained is cooled to 0±2° C.before introducing 2.8 ml of a 96% sulphuric acid solution in a time ofabout 10 minutes. After stirring for about 10 minutes, 184.2 g (1 mol, 1eq) of benzhydrol are introduced in portions at 0° C.±2° C. in 60±15minutes. The reaction medium is maintained in contact for 2 hours atthis temperature.

b) Methyl Diphenylmethylthioacetate (MDMTA)

108.3 g (1.02 mol; 1.02 eq) of methyl thioglycolate are introduced at 0°C.±2° C., and then the reaction mixture is heated to 20° C.±2° C. andkept in contact for 2 hours at this temperature.

c) Methyl 2-diphenylmethylsulfinylacetate (MDMSA)

The reaction medium is heated to 30° C.±2° C., and 100.5±0.5 g of a 35%hydrogen peroxide solution are added. The progress of the oxidationreaction is monitored by HPLC. After 25 hours of contact, the reactionis complete (R1 and R2<0.5%).

d) Recovery of MDMSA

150 ml of distilled water are stirred. A 25% aqueous ammonia solution isadded so as to bring the pH to 8. The aqueous organic phases areseparated, and the aqueous phase is extracted with 2×100 ml ofdichloromethane. The organic phases are then combined and concentratedunder reduced pressure at a temperature of 70° C. The concentrateobtained crystallizes to give, after grinding, a white powder with ayield of 98.0±0.5%.

Examples 2 and 3 Synthesis of MDMSA on a Pilot Scale (100 l) Example 2Synthesis of Crystallized MDMSA

a) Benzhydryl Acetate

A solution of acetic anhydride (8.73 kg; 85.5 mol; 1.05 eq) in methylenechloride (40 l) is prepared at 20° C.±2° C. A 96% sulphuric acidsolution (225 ml; 4.1 mol; 0.05 eq) is then added with a stirring of 100revolutions/min, at 0° C.±5° C. in 5 to 10 minutes. The benzhydrol (15kg; 81.4 mol, 1 eq) is then introduced at 0° C.±2° C. in 1.25 hours. Thereaction mixture is stirred for a contact time of 2 hours.

b) Methyl Diphenylmethylthioacetate (MDMTA)

Methyl thioglycolate (8.81 kg; 82.9 mol; 1.02 eq) is introduced at 0°C.±2° C. in about 10 minutes. The reaction mixture is brought to thetemperature of 20° C.±2° C. and kept at this temperature for a contacttime of 2 hours, with a stirring of 100 revolutions/min.

c) Methyl 2-diphenylmethylsulfinylacetate (MDMSA)

The reaction mixture is then brought to 30° C. before introducingsulphuric acid (450 ml; 8.1 mol; 0.1 eq) with stirring (100revolutions/min), in about 5 to 10 minutes. A 35% hydrogen peroxidesolution (8.19 kg; 84.3 mol; 1.035 eq) is then introduced at 30° C.±2°C. in 1 hour. The contact time is determined by monitoring the reactionby HPLC (cf. Table 1).

d) Recovery of MDMSA

The mixture is cooled to 20° C.±2° C. and then 20 l of water areintroduced. After neutralizing the reaction medium by adding asufficient quantity of NH₄OH so that 8<pH<9, the aqueous and organicphases are separated and the aqueous phase extracted twice with 10 l ofmethylene chloride. The chlorinated phases are washed with 10 l ofwater.

The solvent is distilled under atmospheric pressure and then underreduced pressure, at a jacket temperature of 70° C. When thedistillation is complete, isopropyl acetate (1.8 vol; 42 l) is added andthe whole is cooled to −10° C. After draining and drying under vacuum at45° C., MDMSA is obtained.

TABLE 1 Yield and quality of the MDMSA and of the intermediate productsobtained by this method for trials 1 to 4 (step (ii). Formation ofFormation of Formation of HPLC of benzhydryl acetate MDMTA MDMSA thefinished Yield Trial Time HPLC % Time HPLC % Time HPLC % product % % 1 2h 98.9 2 h 98.5 10 h T = 1 D = 99.7 88 S = 0.3 S = 0.3 11 h T = 0.7 S =0.35 11 h 30 T = 0.3 S = 0.4 2 2 h 99.3 2 h 99.1 11 h 30 T = 0.9 D =99.6 86.4 S = 0.35 S = 0.3 T = 0.1 3 2 h 99.3 2 h 99.0 11 h 30 T = 0 D =99.7 90.1 S = 0.4 S = 0.3 4 2 h 99.3 2 h 99.1 5 h T = 7.2 D = 99.7 90.0S = 0.16 S = 0.3 6 h 30 T = 4.4 S = 0.17 8 h T = 2.3 S = 0.22 9 h T =1.6 S = 0.14 10 h T = 1.15 S = 0.3 11 h T = 0.6 S = 0.38 11 h 30 T = 0.3S = 0.38 D = MDMSA S = Sulphone T = MDMTA

These results demonstrate that the production of benzhydryl acetate andof MDMTA can be reproducible.

The formation of MDMSA takes place in 11 h 30 min and reproduciblygives, after crystallization from isopropyl acetate, a final productwhich is in conformity (R₁ and R₂<0.5%), with a yield of the order of90%.

Example 3 Synthesis of Crude MDMSA

a) Benzhydryl Acetate

A solution of acetic anhydride (8.73 kg; 85.5 mol; 1.05 eq) in methylenechloride (40 l) is prepared at 20° C. A 96% sulphuric acid solution (225ml; 4.1 mol; 0.05 eq) is then added with a stirring of 100revolutions/min, at 0° C.±5° C. in 5 to 10 minutes. The benzhydrol (15kg; 8.4 mol, 1 eq) is then introduced at 0° C.±2° C. in 1.25 hours. Thereaction mixture is stirred for a contact time of 2 hours.

b) Methyl Diphenylmethylthioacetate (MDMTA)

Methyl thioglycolate (8.81 kg; 82.9 mol; 1.02 eq) is introduced at 0° C.in about 10 minutes. The reaction mixture is brought to the temperatureof 20° C.±2° C. and kept at this temperature for a contact time of 2hours, with stirring of 100 revolutions/min.

c) Methyl 2-diphenylmethylsulfinylacetate (MDMSA)

Once the reaction mixture has been brought to 30° C.±2° C., a 35%hydrogen peroxide solution (8.19 kg; 84.3 mol; 1.035 eq) is introducedwith stirring (100 revolutions/min) in 1 hour. The contact time isdetermined by monitoring the reaction by HPLC (cf. Table 2).

d) Recovery of MDMSA

The mixture is cooled to 20° C. and then 20 l of water are introduced.After neutralizing the reaction medium by adding a sufficient quantityof NH₄OH so that 8<pH<9, the aqueous and organic phases are separatedand the aqueous phase extracted twice with 10 l of methylene chloride.The chlorinated phases are washed with 10 l of water.

The solvent is distilled to dryness under atmospheric pressure and thenunder reduced pressure at a jacket temperature of 70° C. in a Moritz®turbosphere.

TABLE 2 Yield and quality of the finished product and of theintermediate products for trials 5 and 6 Formation of Formation ofFormation of HPLC of benzhydryl acetate MDMTA MDMSA the finished YieldTrial Time HPLC % Time HPLC % Time HPLC % product % % 5 2 h 99.6 2 h99.2 35 h T = 0.3 D = 99.12 97.2 S = 0.4 S = 0.44 T = 0.24 6 2 h 99.3 2h 98.9 33 h T = 0.17 D = 99.2 97 S = 0.4 S = 0.4 T = 0.2 D = MDMSA S =Sulphone T = MDMTA

These results show that the steps of formation of benzhydryl acetate andof MDMTA can be reproducible.

The step of oxidation of MDMTA requires a contact time of about 33–35hours and gives an MDMSA product which is in conformity (R₁ andR₂<0.5%), with good yields (of the order of 97%).

1. Method for preparing methyl 2-diphenylmethylsulfinylacetate (MDMSA)comprising the steps of: (i) conversion of benzhydrol intomethyldiphenylmethylthioacetate; and (ii) conversion ofmethyldiphenylmethylthioacetate intomethyl-2-diphenylmethylsulfinylacetate.
 2. Method according to claim 1,in which step (i) comprises the following steps: a1) conversion ofbenzhydrol to benzhydrol carboxylate in an appropriate solvent; b1)conversion of the benzhydrol carboxylate to methyldiphenylmethylthioacetate.
 3. Method according to claim 2, in which thestep (a1) comprises reacting benzhydrol and an acid anhydride in thepresence of an inorganic acid and in an appropriate solvent.
 4. Methodaccording to claim 3, in which the solvent is an aprotic solvent. 5.Method according to claim 4, in which the aprotic solvent is chosen fromchlorinated solvents, aromatic solvents, hydrocarbon solvents andethereal solvents.
 6. Method according to claim 5, in which the aproticsolvent is chosen from chlorinated solvents.
 7. Method according toclaim 6, in which the solvent is dichloromethane.
 8. Method according toclaim 3, in which the acid anhydride is chosen from acetic anhydride,propanoic anhydride and butyric anhydride.
 9. Method according to claim8, in which the acid anhydride is acetic anhydride.
 10. Method accordingto claim 3, in which the inorganic acid is chosen from hydrochloricacid, butyric acid, o-phosphoric acid and sulfuric acid.
 11. Methodaccording to claim 10, in which the inorganic acid is sulfuric acid. 12.Method according to claim 3, in which the quantity of inorganic acidused is from 0.02 to 0.3 molar equivalents relative to the benzhydrol.13. Method according to claim 3, in which the reaction temperature instep a) is between +5° C. and +5° C.
 14. Method according to claim 2, inwhich step b1) comprises bringing the solution obtained in step a) intocontact with methyl thioglycolate.
 15. Method according to claim 14, inwhich the contact time used in step b1) is between 2 and 3 hours. 16.Method according to claim 14, in which the contact temperature used instep b1) is between 15° C. and 25° C.
 17. Method according to claim 1,in which the oxidizing agent is chosen from oxone, potassiumpermanganate, sodium percarbonate, and peroxides.
 18. Method accordingto claim 17, in which the oxidizing agent is hydrogen peroxide. 19.Method according to claim 18, in which the hydrogen peroxide is added inthe form of a 35% aqueous solution.
 20. Method according to claim 1, inwhich the oxidizing agent is used in an amount of 1 to 1.1 molarequivalent.
 21. Method according to claim 1, in which the reactiontemperature in step (ii) is between 28° C. and 37° C.
 22. Methodaccording to claim 3, in which an additional quantity of inorganic acidis added in step (ii).
 23. Method according to claim 22, in which theadditional quantity of inorganic acid is from 0.02 to 0.3 molarequivalents.
 24. Method according to claim 22, in which the contact timein step (ii) is between 10 and 13 hours.
 25. Method according to claim1, which comprises an additional step (iii) recovering the methyl2-diphenyl-methylsulfinylacetate obtained.
 26. Method according to claim25, in which step (iii) comprises a distillation of the solvent todryness.
 27. Method according to claim 25, in which step (iii) comprisesa step of direct crystallization.
 28. Method according to claim 27, inwhich the crystallization solvent is chosen from methanol, ethanol,ethyl acetate, isopropyl acetate and toluene.
 29. Method according toclaim 28, in which the crystallization solvent is isopropyl acetate. 30.Method according to claim 1, in which the successive steps are carriedout in the same reactor without isolation of the intermediate compounds.31. Method for preparing modafinil comprising preparing MDMSA accordingto claim 1.